N,N-disubstituted piperazines

ABSTRACT

N,N-Disubstitued piperazines are prepared by reacting either the appropriately substituted furans or the N-unsubstituted pyrrolidines with aminoalkylpiperazines. The substances according to the invention can be employed as active agents in medicaments, in particular for the production of immunomodulators.

The present invention relates to N,N-disubstituted piperazines, processes for their preparation and their use in medicaments.

The publication US 4 804 751 A discloses polycyclic dicarboximides having an antipsychotic and anxiolytic action.

In most theories about autoimmune diseases, T lymphocytes are mentioned as initiators of many cellular processes which lead to tissue destruction and to symptoms which are associated with specific autoimmune diseases [Paul, E. W. 1984, Fundamental Immunology, Ravens Press, New York]. Rheumatoid arthritis is an example of such a disease and adjuvant-induced arthritis in the rat is regarded as a representative animal model thereof [Lombardino, J. G. 1985, Nonsteroidal Antiinflammatory Drugs, John Wiley & Sons, New York]. For the rat adjuvant arthritis model, it has been shown with the aid of a large number of studies that T cells are involved in the progression of the disease. Additionally, T cells from rats with adjuvant disease transfer this disease to healthy animals in the absence of any source of antigen or other inflammatory factors.

As a consequence, the inhibition of the T cell function or T cell activation should positively affect both adjuvant arthritis in the rat and also the course of the disease in various human autoimmune diseases.

Recently, a serotonin-type receptor was identified on Jurkart cells [Aune, T., M. Kelley, U. A. Ranges, G. E. Bombera, M. P. 1990, J. Immunol. 145, 1826], from which it is assumed that it regulates the T cell function. It is therefore assumed that selective antagonists of this receptor inhibit T cell proliferation.

The present invention relates to N,N-disubstituted piperazines of the general formula (I) ##STR1## in which A and D are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl or trifluoromethoxy, or represent straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms,

R¹ and R² are identical or different and represent hydrogen, halogen, cyano, formyl, phenyl or hydroxyl, or represent straight-chain or branched alkoxy having up to 8 carbon atoms, or represent straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl or halogen, by straight-chain or branched alkoxy having up to 6 carbon atoms or by a group of the formula --NR³ R⁴,

in which

R³ and R⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,

E and L together form a heterocyclic radical of the formula ##STR2## in which R⁵ and R⁶ are identical or different and denote hydrogen, halogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by carboxyl or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,

R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or

R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O,

a denotes a number, 2, 3, 4, 5, 6, or 8

R¹¹ denotes hydrogen, cycloalkyl having 3 to 8 carbon atoms, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part can be substituted up to 3 times by identical or different halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms,

and their salts.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the N,N-disubstituted piperazines can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred salts, for example, are those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts in the context of the present invention are additionally salts of the monovalent metals such as alkali metals and the ammonium salts. Sodium, potassium and ammonium salts are preferred.

The compounds according to the invention exist in stereoisomeric forms, which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as to the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Preferred compounds of the general formula (I) are those in which

A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or

represent straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms,

R¹ and R² are identical or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxyl, or

represent straight-chain or branched alkoxy having up to 6 carbon atoms, or

represent straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl, fluorine, chlorine or bromine, by straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula --NR³ R⁴,

in which

R³ and R⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,

E and L together form a heterocyclic radical of the formula ##STR3## in which R⁵ and R⁶ are identical or different and denote hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is-optionally substituted by carboxyl or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,

R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O,

a denotes a number, 2, 3, 4, 5, 6 or 7,

R¹¹ denotes hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part is substituted up to 3 times by identical or different fluorine, chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl or trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms,

and their salts.

Particularly preferred compounds of the general formula (I) are those

in which

A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms,

R¹ and R² are identical or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxyl, or

represent straight-chain or branched alkoxy having up to 4 carbon atoms, or

represent straight-chain or branched alkyl or alkenyl in each case having up to 4 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl, fluorine, chlorine or bromine, by straight-chain or branched alkoxy having up to 3 carbon atoms or by amino or aminomethyl,

E and L together form a heterocyclic radical of the formula ##STR4## in which R⁵ and R⁶ are identical or different and denote hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl or by straight-chain or branched alkoxy

carbonyl having up to 3 carbon atoms,

R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O,

a denotes a number 2, 3, 4, 5 or 6,

R¹¹ denotes hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part is substituted up to 3 times by identical or different fluorine, chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl or trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms,

and their salts.

Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, which comprise

[A] reacting compounds of the general formula (II) ##STR5## in which A, D, R¹, R², R⁵ and R⁶ have the abovementioned meaning, with compounds of the general formula (III) ##STR6## in which a and R¹¹ have the abovementioned meaning,

in inert solvents, in the presence of a base and/or auxiliary, if appropriate under a protective gas atmosphere, or

[B] converting compounds of the general formula (IV) ##STR7## in which A, D, R¹, R², R⁵ and R⁶ have the abovementioned meaning, first by reaction with compounds of the general formula (V)

    Q--(CH.sub.2).sub.a --S                                    (V)

in which

a has the abovementioned meaning,

Q represents halogen or a typical leaving group, but preferably bromine,

and

S has the abovementioned meaning of Q or represents carboxyl or an activated carboxylic radical,

in inert solvents, if appropriate in the presence of a base,

into the compounds of the general formula (VI) ##STR8## in which A, D, a, R¹, R², R⁵ and R⁶ have the abovementioned meaning, and

T includes the abovementioned scope of meaning of Q and S,

and in a second step, likewise in the presence of a base and of a solvent, reacting with compounds of the general formula (VII) ##STR9## in which R¹¹ has the abovementioned meaning, or

[C] first converting compounds of the general formula (III) by reaction with compounds of the general formula (VIII) ##STR10## in which R⁵ and R⁶ have the abovementioned meaning, into the compounds of the general formula (IX) ##STR11## in which R⁵, R⁶, R¹¹ and a have the abovementioned meaning, and then reacting with anthracenes of the general formula (X) ##STR12## in which A, D, R¹ and R² have the abovementioned meaning, in inert solvents,

and in the case where R⁷ and R⁸ and/or R⁹ and R¹⁰ do not in each case together form the radical of the formula ═O, reducing by customary methods, and optionally varying the abovementioned substituents according to known methods.

The processes according to the invention can be illustrated by way of example by the following reaction schemes: ##STR13##

Suitable solvents for the processes are customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, 1,2-dimethoxyethane or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred.

Bases which can be employed for the processes according to the invention are in general inorganic or organic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, barium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium methoxide or potassium methoxide or potassium tert-butoxide, or lithium diisopropylamide (LDA), or organic amines (trialkyl(C₁ -C₆)amines) such as triethylamine, or heterocycles such as 1,4-diazobicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ alkali metals, such as sodium, or their hydrides such as sodium hydride as bases. Potassium carbonate, sodium hydride, potassium tert-butoxide and cesium carbonate are preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol, preferably from 1 mol to 2 mol, in each case relative to 1 mol of the compounds of the general formulae (III), (V) and (VII).

Suitable auxiliaries for the activation of the carboxylic acid function in the compounds of the general formula (V) and for the Dieis-Alder reaction are Lewis acids such as, for example, zinc chloride, titanium tetrachloride, boron tribromide, aluminum chloride or lithium perchlorate or thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride. Carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphoramidate or methanesulfonyl chloride are additionally suitable, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The processes according to the invention are in general carried out in a temperature range from 0° C. to +180° C., preferably from +20° C. to +150° C.

The process according to the invention is in general carried out at normal pressure. However, it is also possible to carry out the process at elevated pressure or at reduced pressure (e.g. in a range from 0.5 to 5 bar).

Carbonyl functions are in general reduced using complex hydrides, such as lithium aluminum hydride or sodium borohydride, preferably using lithiumaluminum hydride in inert solvents such as ethers or hydrocarbons or their mixtures, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dioxane, in a temperature range from 0° C. to +150° C., preferably from +20° C. to 100° C., at normal pressure.

The abovementioned derivatizations of the substituents R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are in general carried out by methods known from the literature, where the reduction of aldehydes or alkoxycarbonyl compounds to alcohols (a), the reduction of double bonds (b) and the alkylation (c) are to be illustrated by way of example by the following:

a) The reduction of carbonyl compounds to the corresponding alcohols is in general carried out using hydrides, such as lithium aluminum hydride or sodium borohydride, preferably in the case of the alkoxycarbonyl compounds using lithium aluminum hydride and in the case of the aldehydes preferably using sodium borohydride in inert solvents such as ethers, hydrocarbons or alcohols or their mixtures, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dioxane, or alcohols such as ethanol, in the case of the aldehydes preferably using sodium borohydride in ethanol, in a temperature range from 0° C. to +150° C., preferably from +20° C. to +100° C., at normal pressure.

The reduction of a double bond is in general carried out by hydrogenation with hydrogen in the presence of a catalyst such as, for example, platinum or platinum oxides, rhodium, ruthenium, chlorotris(triphenylphosphine)rhodium, or palladium on animal carbon, preferably using palladium on animal carbon in a temperature range from 0° C. to +150° C., preferably from +25° C. to +100° C.

b) Suitable solvents for the hydrogenation are protic solvents such as, for example, methanol, ethanol and/or aprotic solvents such as, for example, tetrahydrofuran, toluene, dimethylformamide, methylene chloride, dioxane or ethyl acetate.

The hydrogenation is carried out at a pressure from 1 to 300 atm, preferably at 1 to 20 atm.

c) The alkylation is in general carried out in one of the abovementioned solvents using alkylating agents such as, for example, (C₁ -C₈)-alkyl halides, sulfonic acid esters or substituted or unsubstituted (C₁ -C₈)-dialkyl or (C₁ -C₈)-diaryl sulfates, preferably methyl iodide, p-toluenesulfonic acid esters or dimethyl sulfate.

The compounds of the general formula (II) are known in some cases or are new and can then be prepared, for example, by reacting anthracene or its substituted derivatives, with maleic anhydride or its substituted derivatives, such as, for example, citraconic anhydride, in one of the abovementioned solvents, preferably toluene or xylene, in a temperature range of 100°-150° C., preferably at 140° C., or reacting in an aprotic solvent, such as, for example, methylene chloride, in the presence of one of the abovementioned Lewis acids, for example aluminum chloride, in a temperature range from 0° C. to 80° C., preferably at room temperature to +40° C.

The compounds of the general formulae (III), (V), (VII), (VIII) and (X) are known per se or can be prepared by customary methods.

The compounds of the general formula (IX) are known in some cases or are new and can then be prepared as described above.

The compounds of the general formula (IV) are likewise known in some cases or are new and can then be prepared, for example, as described above for the compounds of the general formula (II), by reaction of anthracene or its substituted derivatives with substituted or unsubstituted succinimides.

The compounds of the general formula (VI) are new and can be prepared, for example, as described above.

The compounds of the general formula (I) according to the invention surprisingly show an immunomodulating action.

They are thus suitable for the treatment of rheumatoid arthritis, multiple sclerosis, muscle weakness, disseminated lupus erythematosus, Basedow's disease, psoriasis, transplant rejection, Hashimoto's thyroiditis, inflammatory gastric diseases, inflammations of the gastrointestinal tract, primary cirrhosis of the liver and autoimmune hemolytic anemia.

Adjuvant arthritis model in the rat

Freund's adjuvant (FA) is prepared by addition of 10 mg/ml of heat-killed Mycobacterium butyricum to extra-heavy mineral oil. Lewis rats receive a 0.1 ml injection of FA (1 mg/animal) subcutaneously in the right hind paw. An acute inflammation takes place there, which is characterized by reddening, edema and a predominant neutrophilic cell infiltration (primary reaction). Tumescent areas in the treated paw on day 5 are followed between day 10-12 by an increase in the swelling (chronic inflammatory reaction) and the occurrence of a swelling in the opposite untreated paw (secondary immune response).

The cell infiltration of the chronic inflammation and the second immune response are mainly mononuclear, which indicates the presence of T-cell mediated immunity. The animals are observed daily, and the swelling is measured in millimeters on days 12 and 16 using a hand-adjustable micrometer. The swelling reaches its peak on the 16th day, on which the animals are sacrificed and tissue samples are taken for histological evaluation.

The extent of the swelling is determined by calculation of the greatest difference in the malleolus diameter between the 16th and the 0th day.

The animals receive the compounds according to the invention in a suspension of 5% polyethylene glycol and 0.5% Tween 80 in phosphate buffer solution p.o. or i.p. on days 0, 1, 2, 5, 7, 9, 12 and 14 [cf. for this purpose L. Sokoloff, 1984, Int. Rev. Exp. Pathol. 26, 107; M. E. J. Bittingham et al., 1989, J. Exp. Med. 171, 339; K. M. Connolly et al., 1989, Agents and Actions 27, 328].

                  TABLE A                                                          ______________________________________                                                     Inhibition of the                                                              swelling in % after                                                            administration of                                                  Ex. No.     10 mg/kg i.p.                                                      ______________________________________                                          5          24                                                                  6          24                                                                 13           2                                                                 16          13                                                                 20          79                                                                 21            0.5                                                              22          80                                                                             (at 20 mg)                                                         ______________________________________                                    

The in vitro activity of the compounds according to the invention results from their capability to inhibit T cell proliferation, which is previously stimulated by serotonin.

Inhibition of 5-HT-dependent T cell proliferation

Peripheral mononuclear blood cells (PBMC) are obtained from the buffy coat of the blood of healthy subjects. After isolation by means of isolymph gradients (Pharmacia), the PBMC are washed twice and used directly. Purified T cells are obtained by E rosette formation with sheep erythrocytes [cf. Blue, M. -L., J. F. Daley, H. Levine, K. A. Craig and S. F. Schlossmann, 1986, Biosynthesis and surface expression of T8 by peripheral blood T4+ cells in vitro, J. Immunol. 137, 1202]. Monocytes are partially removed by adhesion to tissue culture plates or flasks. PBMC, T cells or purified T cells (depleted in monocytes) at 5×10⁵ /ml, 100 μl/well are cultured in RPMI 1640 medium with 10% fetal calf serum (GIBCO) and L-glutamine in 96-well microculture plates (Becton-Dickinson) under a 5% CO₂ atmosphere at 37° C. for 7 days. The cultures are treated with 1 μCi of ³ H-thymidine for 6 h on the 7th day and collected on filter paper, and the incorporated radioactivity is determined by means of liquid scintillation counting.

The test substances are dissolved in 10 mM HCl in order to achieve a final concentration of 1 mM in each case. The compounds are diluted serially 3× with medium in order to obtain a final concentration between 33 μM-0.1 μM. PWM (1:200, pokeweed mitogen) and 5-HT (100 μM, serotonin), which contain the test substances, are added to monocyte-free human T cells. The positive control (maximum proliferation) is obtained from cultures containing T cells, PWM and 5-HT. The negative control (minimal proliferation) is obtained from cultures containing T cells and PWM without 5-HT. The inhibitory activity of the test substances is expressed as the IC₅₀ in μM.

(see also WO 92/04015)

                  TABLE B                                                          ______________________________________                                                Ex. No.                                                                               IC.sub.50                                                        ______________________________________                                                 1     >10                                                                      2     >10                                                                      3     >10                                                                      4     >10                                                                      5      2                                                                       6      3                                                                       8     50                                                                       9     20                                                                      10     30                                                                      12     >10                                                                     15      2                                                                      16      5                                                                      17     >10                                                                     18      2                                                                      19      5                                                                      20       0.5                                                                   21       0.5                                                                   22     10                                                                      23       0.1                                                                   24      6                                                                      26      1                                                               ______________________________________                                    

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this case, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, optionally using emulsifiers and/or dispersants, it being possible, for example, where water is used as the diluent, optionally to use organic solvents as auxiliary solvents.

Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid excipient materials.

In general, it has proven advantageous in the case of intravenous administration to administer amounts from 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to achieve effective results, and in the case of oral administration the dose is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may sometimes be necessary to deviate from the amounts mentioned, in particular depending on the body weight or on the type of application route, on individual behavior toward the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.

Starting Compounds Example I

9,10-Dihydro-9,10[3',4']-furanoanthracene-12,14(11H,15H)-dione ##STR14##

180 g (1.01 mol) of anthracene are suspended in 1000 ml of xylene together with 100 g (1.02 mol) of maleic anhydride. The suspension goes into solution on heating to 140° C. and precipitates again after boiling under reflux for 10 min. After cooling to room temperature, the precipitated cream-colored crystals are washed with xylene and ether and dried.

Melting point: 261°-263° C. Yield: 259.9 g (92.8%)

Example II

3-[4-[bis-(4-Fluorophenyl)-methylpiperazin-1-yl]-propionitrile ##STR15##

21.2 g (0.073 mol) of 1-bis-(4-fluorophenyl)methylpiperazine (Janssen) are stirred with 100 ml of toluene in an argon-flushed flask; 0.9 ml of DBU is added to this mixture and it is stirred. 8.5 ml (0.129 mol) of acrylonitrile are added dropwise to the resulting solution in about 15 min below 30° C. (ice-bath cooling, slightly exothermic). The solution is allowed to stand at room temperature for 3 days and is concentrated in a rotary evaporator at about 40° C./20 mbar. About 30 ml of ether/petroleum ether 1:1 are added to the oil which remains and it is triturated. The cream-colored crystals are filtered off with suction, washed with ether/petroleum ether and dried.

Melting point: 71°-73° C. Yield: 19.2 g (76.5% of theory)

Example III

3-[4-[bis-(4-Fluorophenyl)-methyl]-piperazin-1-yl]propylamine ##STR16##

The hydrogenatation of 18.5 g (0.0542 mol) of the compound from Example II is carried out in a steel autoclave in 100 ml of methanol and 30 ml of liquid ammonia with the addition of 4 g of Ra Ni at 60-70 bar and 70° C. over the course of about 6 hours. After filtering off the catalyst, it is washed with methanol, the residue is discarded and the mother liquor is concentrated in a rotary evaporator at about 35° C. in a water jet vacuum. The colorless oil obtained is further reacted without additional purification. Yield: 18 g (97% of theory)

PREPARATION EXAMPLES EXAMPLE 1 13-{3-[4-(bis-4-Fluorophenyl)-methyl)-piperazin-1-yl]-propyl}-9,10-dihydro-9,10-[3'-4']pyrroloanthracene-12,14(11H,15H)dione ##STR17##

5.2 g (0.015 mol) of the compound from Example III, dissolved in 15 ml of xylene, are added dropwise to a suspension of 4.1 g (0.015 mol) of the compound from Example I in 100 ml of xylene and the mixture is boiled in a water separator for 1.5 h. The solution is cooled to room temperature and concentrated in a rotary evaporator at 50° C./20 mbar. The oil which remains is triturated with ether/petroleum ether 1:1. The cream-colored crystals are filtered off with suction and dried.

Melting point: 188°-190° C. Yield: 8.1 g (90.3% of theory)

The examples shown in Table 1 are prepared in analogy to the procedure of Example I:

                  TABLE 1                                                          ______________________________________                                          ##STR18##                                                                     Ex. No.                                                                               R.sup.2 R.sup.5                                                                              a   R.sup.11       m.p. °C.                        ______________________________________                                         2      H       H     3                                                                                   ##STR19##     182-184                                3      H       H     3                                                                                   ##STR20##     188-190                                4      H       H     3   CH(C.sub.6 H.sub.5).sub.2                                                                     200-203                                5      H       H     3   (CH.sub.2).sub.2 -o-CF.sub.3C.sub.6 H.sub.4                                                   141-143                                6      H       H     3   CH.sub.2 -p-C(CH.sub.3).sub.3C.sub.6 H.sub.4                                                  164-166                                       H       H     3                                                                                   ##STR21##     131-133                                8      H       H     3                                                                                   ##STR22##     170-172                                9      H       H     3   (CH.sub.2)CH.sub.3                                                                            118-120                                10     H       H     3                                                                                   ##STR23##     120-122                                11     CH.sub.3                                                                               H     3   CH(C.sub.6 H.sub.5).sub.2                                                                     194-196                                12     H       H     3   CH(p-FC.sub.6 H.sub.4).sub.2                                                                  188-190                                ______________________________________                                    

EXAMPLE 13 13-{3-[4(bis-4-Fluorophenyl)-methyl]-piperazin-1-yl]propyl}-9,10,11,12,14,15-hexahydro-9,10[3'4']pyrroloanthracene ##STR24##

6.9 g (0.011 mol) of the compound from Example 1 are introduced under argon in portions in the course of 10 minutes into a suspension of 1.3 g (0.034 mol) of lithium aluminum hydride in 150 ml of dioxane p.A. at 90° C. with vigorous stirring. The suspension is boiled under reflux (100° C.) for 6 h, cooled to room temperature and cautiously treated dropwise with 1.3 ml of H₂ O with stirring. 3.9 ml of dil. potassium hydroxide solution are then added dropwise and the mixture is boiled for 10 minutes and filtered hot with suction. The precipitate which remains is washed with dioxane and discarded. The mother liquor is cooled to room temperature and concentrated in a rotary evaporator at about 40° C./20 mbar. The oily residue is treated with methylene chloride/water, the mixture is extracted twice with methylene chloride, and the organic phase is washed twice with H₂ O and dried over Na₂ SO₄ and concentrated in a rotary evaporator at 35° C./20 mbar. 6.59 g of oil are obtained.

The oil obtained is dissolved in 80 ml of p.A. ether and 2.65 g of maleic acid (0.0228 mol) dissolved in p.A. THF are added. The white crystalline precipitate is filtered off with suction and washed with ether.

Melting point: 198°-200° C. Yield: 8.2 g (89%)

The compounds shown in Table 2 are prepared in analogy to the procedure of Example 13:

                                      TABLE 2                                      __________________________________________________________________________      ##STR25##                                                                     Ex. No.                                                                              R.sup.2                                                                             R.sup.5                                                                           a  R.sup.11      m.p. °C.                                                                         Salt                                   __________________________________________________________________________     14    H    H  3                                                                                  ##STR26##    162-165 (dec.)                                                                          2 × B                            15    H    H  3                                                                                  ##STR27##    95-98                                           16    H    H  3  (CH.sub.2).sub.2 -o-CF.sub.3C.sub.6 H.sub.4                                                  195-197 dec.                                                                            2.5 × B                          17    H    H  4                                                                                  ##STR28##    178-180                                         18    H    H  3  CH.sub.2 -p-C(CH.sub.3).sub.3C.sub.6 H.sub.                                                  199-201 (dec.)                                                                          2 × B                            19    H    H  3                                                                                  ##STR29##    190-192 (dec.)                                                                          2 × B                            20    CH.sub.3                                                                            H  3  CH(C.sub.6 H.sub.5).sub.2                                                                    198-200 (dec.)                                                                          2 × B                            21    H    H  3  CH(C.sub.6 H.sub.5).sub.2                                                                    119-121                                         22    H    H  1  H             146-148                                         23    H    H  3  (CH.sub.2).sub.3CH(p-FC.sub.6 H.sub.4).sub.2                                                 188-190 (dec.)                                                                          2 × B                            24    H    H  3                                                                                  ##STR30##    181-183 (dec.)                                                                          2 × B                            25    H    H  3  (CH.sub.2).sub.2CH.sub.3                                                                     148-151 (dec.)                                                                          1.5 × B                          26    H    H  3                                                                                  ##STR31##    75-80                                           27    CH.sub.3                                                                            H  3  CH(C.sub.6 H.sub.5).sub.2                                                                    198-200 (dec.)                                                                          2 × B                            __________________________________________________________________________      B = H.sub.2 OCCHCHCO.sub.2 H                                              

We claim:
 1. An N,N-disubstituted piperazine of the formula (I) ##STR32## in which A and D are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxyl, nitro, trifluoromethyl or trifluoromethoxy, or represent straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms,R¹ and R² are identical or different and represent hydrogen, halogen, cyano, formyl, phenyl or hydroxyl, orrepresent straight-chain or branched alkoxy having up to 8 carbon atoms, or represent straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl or halogen, by straight-chain or branched alkoxy having up to 6 carbon atoms or by a group of the formula --NR³ R⁴, in which R³ and R⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, E and L together form a heterocyclic radical of the formula ##STR33## in which R⁵ and R⁶ are identical or different and denote hydrogen, halogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by carboxyl or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O, a denotes a number 2, 3, 4, 5, 6, 7 or 8, R¹¹ denotes hydrogen, cycloalkyl having 3 to 8 carbon atoms, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part can be substituted up to 3 times by identical or different halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.
 2. An N,N-disubstituted piperazine or salt thereof as claimed in claim 1in which A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl, trifluoromethoxy orrepresent straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms, R¹ and R² are identical or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxyl, orrepresent straight-chain or branched alkoxy having up to 6 carbon atoms, or represent straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl, fluorine, chlorine or bromine, by straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula --NR³ R⁴, in which R³ and R⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, E and L together form a heterocyclic radical of the formula ##STR34## in which R⁵ and R⁶ are identical or different and denote hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O, a denotes a number 2, 3, 4, 5, 6 or 7, R¹¹ denotes hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part is substituted up to 3 times by identical or different fluorine, chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms.
 3. An N,N-disubstituted piperazine or salt thereof as claimed in claim 1in which A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms, R¹ and R² are identical or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxyl, orrepresent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl or alkenyl in each case having up to 4 carbon atoms, each of which is optionally substituted up to 2 times by identical or different hydroxyl, nitro, phenyl, fluorine, chlorine or bromine, by straight-chain or branched alkoxy having up to 3 carbon atoms or by amino or aminomethyl, E and L together form a heterocyclic radical of the formula ##STR35## in which R⁵ and R⁶ are identical or different and denote hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl or by straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R⁷ and R⁸ and/or R⁹ and R¹⁰ in each case together form the radical of the formula ═O, a denotes a number 2, 3, 4, 5 or 6, R¹¹ denotes hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted up to 2 times by identical or different phenyl, which for its part is substituted up to 3 times by identical or different fluorine, chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms.
 4. A composition for the treatment of rheumatoid arthritis, inflammatory gastric diseases and inflammation of the gastrointestinal tract comprising an amount effective therefor of a compound or salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
 5. A method of treating rheumatoid arthritis, inflammatory gastric diseases and inflammations of the gastrointestinal tract, in a patient afflicted therewith which comprises administering to such patient an amount effective therefor of a compound or salt thereof according to claim
 1. 6. The method according to claim 5, wherein the patient is afflicted with rheumatoid arthritis.
 7. The method according to claim 5, wherein the patient is afflicted with inflammatory gastric diseases.
 8. The method according to claim 5, wherein the patient is afflicted with inflammations of the gastrointestinal tract.
 9. The method according to claim 5, wherein such compound is ##STR36## or a pharmaceutically acceptable salt thereof. 